tbuckley/cabot-search huggingface dataset:
Manjula Arora case: united we stand
Authors: Emily L Russell
Journal: BMJ (2022)

<h3>Background:</h3> Atrial function is an integral part of cardiac function that is often neglected. The presence of left ventricule hypertrophy (LVH) due to arterial hypertension may impair atrial function. However, it has also been suggested that physical training attenuates the age-associated impairment of diastolic filling. This study investigated whether mechanical dysfunction in the left atrium (LA) is present in patients with either physiological or pathological LVH, using two-dimensional strain rate imaging (2D strain echocardiography; 2DSE). <h3>Methods:</h3> Standard echocardiography, exercise stress echo and 2DSE of the left atrium were performed in 40 patients with arterial hypertension, 45 age-matched elite athletes (&gt;40 years) and 25 healthy sedentary controls. Atrial longitudinal strain was performed from the apical views for the basal segments of the LA septum, lateral wall and roof. <h3>Results:</h3> LV mass index and ejection fraction were comparable between patients with either physiological or pathological LVH. Elite athletes showed increased LV end-diastolic diameter, end-diastolic volume and stroke volume, whereas circumferential end-systolic stress was higher in patients with hypertension. LA diameter and maximum volume were increased but similar between the two groups of patients with LVH. LA active emptying volume and fraction were both higher in patients with hypertension. Conversely, peak systolic myocardial atrial strain was significantly reduced in patients with pathological LVH compared with controls and athletes for all the analysed atrial segments (p&lt;0.0001). Using multivariate analysis, LV end-diastolic volume/body surface area (BSA) (β coefficient 0.52; p&lt;0.0001) and LV mass (β = 0.48; p&lt;0.001) in athletes emerged as the only independent determinants of LA lateral wall peak systolic strain. In contrast, in patients with hypertension, an independent negative association of LA lateral wall peak systolic strain with both LV mass (β = −0.42; p&lt;0.001) and circumferential end-systolic stress (β = −0.43; p&lt;0.001) was found. In addition, in the overall population of patients with LVH, LA lateral wall systolic strain (β = 0.49; p&lt;0.0001) was a powerful independent predictor of maximum workload during exercise testing. <h3>Conclusions:</h3> 2DSE represents a promising, non-invasive, simple and reproducible technique to assess LA myocardial function in patients with either physiological or pathological LVH. LA myocardial deformation is impaired in patients with hypertension compared with age-matched sedentary controls and elite athletes, and is closely associated with functional capacity during effort.
Intuitive physics learning in a deep-learning model inspired by developmental psychology
Authors: Luis S. Piloto, Ari Weinstein, Peter Battaglia, Matthew Botvinick
Journal: Nature Human Behaviour (2022)

'Intuitive physics' enables our pragmatic engagement with the physical world and forms a key component of 'common sense' aspects of thought. Current artificial intelligence systems pale in their understanding of intuitive physics, in comparison to even very young children. Here we address this gap between humans and machines by drawing on the field of developmental psychology. First, we introduce and open-source a machine-learning dataset designed to evaluate conceptual understanding of intuitive physics, adopting the violation-of-expectation (VoE) paradigm from developmental psychology. Second, we build a deep-learning system that learns intuitive physics directly from visual data, inspired by studies of visual cognition in children. We demonstrate that our model can learn a diverse set of physical concepts, which depends critically on object-level representations, consistent with findings from developmental psychology. We consider the implications of these results both for AI and for research on human cognition.
The X-Linked Helicase DDX3X Is Required for Lymphoid Differentiation and MYC-Driven Lymphomagenesis
Authors: Marion Lacroix, Hugues Beauchemin, Jennifer Fraszczak, Julie Ross, Peiman Shooshtarizadeh, Riyan Chen, Tarik Möröy
Journal: Cancer Research (2022)

Abstract The X-linked gene DDX3X encodes an RNA helicase that is mutated at high frequencies in several types of human B-cell lymphoma. Females have two active DDX3X alleles and males carry a DDX3Y homolog on the Y chromosome. We show here that pan-hematopoietic, homozygous deletion of Ddx3x in female mice perturbs erythropoiesis, causing early developmental arrest. However, both hemizygous male and heterozygous female embryos develop normally, suggesting that one Ddx3x allele is sufficient for fetal hematopoietic development in females and that the Ddx3y allele can compensate for the loss of Ddx3x in males. In adult mice, DDX3X deficiency altered hematopoietic progenitors, early lymphoid development, marginal zone and germinal center B cells, and lymphomagenesis in a sex-dependent manner. Loss of both Ddx3x alleles abrogated MYC-driven lymphomagenesis in females, whereas Ddx3x deletion in males did not affect the formation of B-cell lymphoma in both mouse models. Moreover, tumors that appeared in male mice lacking DDX3X showed upregulated expression of DDX3Y, indicating a critical requirement for DDX3 activity for lymphomagenesis. These data reveal sex-specific roles of DDX3X in erythro- and lymphopoiesis as well as in MYC-driven lymphomagenesis. Significance: The sex-dependent effects of DDX3X deficiency in malignant transformation of B cells and the compensatory role of DDX3Y support inhibition of DDX3 as a treatment strategy for MYC-driven B-cell lymphoma.
Consensus-based development of a causal attribution system for post-ERCP adverse events
Authors: Nauzer Forbes, B Joseph Elmunzer, Rajesh N Keswani, Robert J Hilsden, Matt Hall, John T Anderson, Marianna Arvanitakis, Yen-I Chen, Anna Duloy, Grace H Elta, Jennifer L Maranki, Klaus Mergener, Bret T Petersen, Amrita Sethi, Peter D Siersema, Zachary L Smith, Jennifer J Telford, Frances Tse, Peter B Cotton, Sachin Wani
Journal: Gut (2022)
A clinician perspective on the treatment of chronic myeloid leukemia in the chronic phase
Authors: Valentin García-Gutiérrez, Massimo Breccia, Elias Jabbour, Michael Mauro, Jorge E. Cortes
Journal: Journal of Hematology & Oncology (2022)

Tyrosine kinase inhibitors (TKIs) have vastly improved long-term outcomes for patients with chronic myeloid leukemia (CML). After imatinib (a first-generation TKI), second- and third-generation TKIs were developed. With five TKIs (imatinib, dasatinib, bosutinib, nilotinib, and ponatinib) targeting BCR::ABL approved in most countries, and with the recent approval of asciminib in the USA, treatment decisions are complex and require assessment of patient-specific factors. Optimal treatment strategies for CML continue to evolve, with an increased focus on achieving deep molecular responses. Using clinically relevant case studies developed by the authors of this review, we discuss three major scenarios from the perspective of international experts. Firstly, this review explores patient-specific characteristics that affect decision-making between first- and second-generation TKIs upon initial diagnosis of CML, including patient comorbidities. Secondly, a thorough assessment of therapeutic options in the event of first-line treatment failure (as defined by National Comprehensive Cancer Network and European LeukemiaNet guidelines) is discussed along with real-world considerations for monitoring optimal responses to TKI therapy. Thirdly, this review illustrates the considerations and importance of achieving treatment-free remission as a treatment goal. Due to the timing of the writing, this review addresses global challenges commonly faced by hematologists treating patients with CML during the COVID-19 pandemic. Lastly, as new treatment approaches continue to be explored in CML, this review also discusses the advent of newer therapies such as asciminib. This article may be a useful reference for physicians treating patients with CML with second-generation TKIs and, as it is focused on the physicians' international and personal experiences, may give insight into alternative approaches not previously considered.
Exploring the conceptual framework and measurement model of intrinsic capacity defined by the World Health Organization: A scoping review
Authors: K. Koivunen, L.A. Schaap, E.O. Hoogendijk, L.J. Schoonmade, M. Huisman, N.M. van Schoor
Journal: Ageing Research Reviews (2022)

WHO has defined intrinsic capacity (IC) as the composite of all physical and mental capacities of an individual covering five subdomains: cognition, locomotion, sensory, vitality, and psychological. Despite this well accepted definition, the conceptual and measurement model of IC remains unclear, which hampers a standardized operationalization of the construct. We performed a scoping review to give a comprehensive overview of the extent to which the current literature of IC addresses and assumes the conceptual framework and measurement model of IC as reflective or formative. For inclusion, we considered all types of articles that were published in peer-reviewed journals except for protocol articles. A systematic search of 6 databases from different disciplines led to the inclusion of 31 papers. We found inconsistency and gaps in the descriptions of IC. Most of the papers did not define the measurement model. In the conceptual background and validation articles, we identified descriptions of both reflective and formative measurement models while in empirical studies applying IC measurements the underlying assumptions remained mainly unclear. Defining a measurement model is not merely a theoretical matter but influences the operationalization and validation processes of the construct. This study raised questions about the most fundamental features of the IC construct and discusses whether IC should be considered as an underlying latent trait of all capacities (reflective construct) or an aggregate summary measure of the subdomain capacities (formative construct).
<i>KRAS</i>‐G12D mutation drives immune suppression and the primary resistance of anti‐PD‐1/PD‐L1 immunotherapy in non‐small cell lung cancer
Authors: Chengming Liu, Sufei Zheng, Zhanyu Wang, Sihui Wang, Xinfeng Wang, Lu Yang, Haiyan Xu, Zheng Cao, Xiaoli Feng, Qi Xue, Yan Wang, Nan Sun, Jie He
Journal: Cancer Communications (2022)

Abstract Background Although immune checkpoint inhibitors (ICIs) against programmed cell death protein 1 (PD‐1) and its ligand PD‐L1 have demonstrated potency towards treating patients with non‐small cell lung carcinoma (NSCLC), the potential association between Kirsten rat sarcoma viral oncogene homolog ( KRAS ) oncogene substitutions and the efficacy of ICIs remains unclear. In this study, we aimed to find point mutations in the KRAS gene resistant to ICIs and elucidate resistance mechanism. Methods The association between KRAS variant status and the efficacy of ICIs was explored with a clinical cohort ( n = 74), and confirmed with a mouse model. In addition, the tumor immune microenvironment (TIME) of KRAS ‐mutant NSCLC, such as CD8 + tumor‐infiltrating lymphocytes (TILs) and PD‐L1 level, was investigated. Cell lines expressing classic KRAS substitutions were used to explore signaling pathway activation involved in the formation of TIME. Furthermore, interventions that improved TIME were developed to increase responsiveness to ICIs. Results We observed the inferior efficacy of ICIs in KRAS ‐G12D‐mutant NSCLC. Based upon transcriptome data and immunostaining results from KRAS ‐mutant NSCLC, KRAS ‐G12D point mutation negatively correlated with PD‐L1 level and secretion of chemokines CXCL10/CXCL11 that led to a decrease in CD8 + TILs, which in turn yielded an immunosuppressive TIME. The analysis of cell lines overexpressing classic KRAS substitutions further revealed that KRAS ‐G12D mutation suppressed PD‐L1 level via the P70S6K/PI3K/AKT axis and reduced CXCL10/CXCL11 levels by down‐regulating high mobility group protein A2 (HMGA2) level. Notably, paclitaxel, a chemotherapeutic agent, upregulated HMGA2 level, and in turn, stimulated the secretion of CXCL10/CXCL11. Moreover, PD‐L1 blockade combined with paclitaxel significantly suppressed tumor growth compared with PD‐L1 inhibitor monotherapy in a mouse model with KRAS ‐G12D‐mutant lung adenocarcinoma. Further analyses revealed that the combined treatment significantly enhanced the recruitment of CD8 + TILs via the up‐regulation of CXCL10/CXCL11 levels. Results of clinical study also revealed the superior efficacy of chemo‐immunotherapy in patients with KRAS ‐G12D‐mutant NSCLC compared with ICI monotherapy. Conclusions Our study elucidated the molecular mechanism by which KRAS ‐G12D mutation drives immunosuppression and enhances resistance of ICIs in NSCLC. Importantly, our findings demonstrate that ICIs in combination with chemotherapy may be more effective in patients with KRAS ‐G12D‐mutant NSCLC.
Regulatory enhancer profiling of mesenchymal-type gastric cancer reveals subtype-specific epigenomic landscapes and targetable vulnerabilities
Authors: Shamaine Wei Ting Ho, Taotao Sheng, Manjie Xing, Wen Fong Ooi, Chang Xu, Raghav Sundar, Kie Kyon Huang, Zhimei Li, Vikrant Kumar, Kalpana Ramnarayanan, Feng Zhu, Supriya Srivastava, Zul Fazreen Bin Adam Isa, Chukwuemeka George Anene-Nzelu, Milad Razavi-Mohseni, Dustin Shigaki, Haoran Ma, Angie Lay Keng Tan, Xuewen Ong, Ming Hui Lee, Su Ting Tay, Yu Amanda Guo, Weitai Huang, Shang Li, Michael A Beer, Roger Sik Yin Foo, Ming Teh, Anders Jacobsen Skanderup, Bin Tean Teh, Patrick Tan
Journal: Gut (2022)

Objective Gastric cancer (GC) comprises multiple molecular subtypes. Recent studies have highlighted mesenchymal-subtype GC (Mes-GC) as a clinically aggressive subtype with few treatment options. Combining multiple studies, we derived and applied a consensus Mes-GC classifier to define the Mes-GC enhancer landscape revealing disease vulnerabilities. Design Transcriptomic profiles of ~1000 primary GCs and cell lines were analysed to derive a consensus Mes-GC classifier. Clinical and genomic associations were performed across &gt;1200 patients with GC. Genome-wide epigenomic profiles (H3K27ac, H3K4me1 and assay for transposase-accessible chromatin with sequencing (ATAC-seq)) of 49 primary GCs and GC cell lines were generated to identify Mes-GC-specific enhancer landscapes. Upstream regulators and downstream targets of Mes-GC enhancers were interrogated using chromatin immunoprecipitation followed by sequencing (ChIP-seq), RNA sequencing, CRISPR/Cas9 editing, functional assays and pharmacological inhibition. Results We identified and validated a 993-gene cancer-cell intrinsic Mes-GC classifier applicable to retrospective cohorts or prospective single samples. Multicohort analysis of Mes-GCs confirmed associations with poor patient survival, therapy resistance and few targetable genomic alterations. Analysis of enhancer profiles revealed a distinctive Mes-GC epigenomic landscape, with TEAD1 as a master regulator of Mes-GC enhancers and Mes-GCs exhibiting preferential sensitivity to TEAD1 pharmacological inhibition. Analysis of Mes-GC super-enhancers also highlighted NUAK1 kinase as a downstream target, with synergistic effects observed between NUAK1 inhibition and cisplatin treatment. Conclusion Our results establish a consensus Mes-GC classifier applicable to multiple transcriptomic scenarios. Mes-GCs exhibit a distinct epigenomic landscape, and TEAD1 inhibition and combinatorial NUAK1 inhibition/cisplatin may represent potential targetable options.
A sequence-based global map of regulatory activity for deciphering human genetics
Authors: Kathleen M. Chen, Aaron K. Wong, Olga G. Troyanskaya, Jian Zhou
Journal: Nature Genetics (2022)

Abstract Epigenomic profiling has enabled large-scale identification of regulatory elements, yet we still lack a systematic mapping from any sequence or variant to regulatory activities. We address this challenge with Sei, a framework for integrating human genetics data with sequence information to discover the regulatory basis of traits and diseases. Sei learns a vocabulary of regulatory activities, called sequence classes, using a deep learning model that predicts 21,907 chromatin profiles across &gt;1,300 cell lines and tissues. Sequence classes provide a global classification and quantification of sequence and variant effects based on diverse regulatory activities, such as cell type-specific enhancer functions. These predictions are supported by tissue-specific expression, expression quantitative trait loci and evolutionary constraint data. Furthermore, sequence classes enable characterization of the tissue-specific, regulatory architecture of complex traits and generate mechanistic hypotheses for individual regulatory pathogenic mutations. We provide Sei as a resource to elucidate the regulatory basis of human health and disease.
Reduced neural feedback signaling despite robust neuron and gamma auditory responses during human sleep
Authors: Hanna Hayat, Amit Marmelshtein, Aaron J. Krom, Yaniv Sela, Ariel Tankus, Ido Strauss, Firas Fahoum, Itzhak Fried, Yuval Nir
Journal: Nature Neuroscience (2022)

Abstract During sleep, sensory stimuli rarely trigger a behavioral response or conscious perception. However, it remains unclear whether sleep inhibits specific aspects of sensory processing, such as feedforward or feedback signaling. Here, we presented auditory stimuli (for example, click-trains, words, music) during wakefulness and sleep in patients with epilepsy, while recording neuronal spiking, microwire local field potentials, intracranial electroencephalogram and polysomnography. Auditory stimuli induced robust and selective spiking and high-gamma (80–200 Hz) power responses across the lateral temporal lobe during both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. Sleep only moderately attenuated response magnitudes, mainly affecting late responses beyond early auditory cortex and entrainment to rapid click-trains in NREM sleep. By contrast, auditory-induced alpha–beta (10–30 Hz) desynchronization (that is, decreased power), prevalent in wakefulness, was strongly reduced in sleep. Thus, extensive auditory responses persist during sleep whereas alpha–beta power decrease, likely reflecting neural feedback processes, is deficient. More broadly, our findings suggest that feedback signaling is key to conscious sensory processing.
DeepLoop robustly maps chromatin interactions from sparse allele-resolved or single-cell Hi-C data at kilobase resolution
Authors: Shanshan Zhang, Dylan Plummer, Leina Lu, Jian Cui, Wanying Xu, Miao Wang, Xiaoxiao Liu, Nachiketh Prabhakar, Jatin Shrinet, Divyaa Srinivasan, Peter Fraser, Yan Li, Jing Li, Fulai Jin
Journal: Nature Genetics (2022)
Systematic identification of cell-fate regulatory programs using a single-cell atlas of mouse development
Authors: Lijiang Fei, Haide Chen, Lifeng Ma, Weigao E, Renying Wang, Xing Fang, Ziming Zhou, Huiyu Sun, Jingjing Wang, Mengmeng Jiang, Xinru Wang, Chengxuan Yu, Yuqing Mei, Danmei Jia, Tingyue Zhang, Xiaoping Han, Guoji Guo
Journal: Nature Genetics (2022)
People of all ages benefit from drugs to lower blood pressure
Authors: Helen Saul, Deniz Gursul, Samantha Cassidy, Kazem Rahimi
Journal: BMJ (2022)

The studyThe Blood Pressure Lowering Treatment Trialists' Collaboration. Age-stratified and blood-pressure-stratified effects of blood-pressure-lowering pharmacotherapy for the prevention of cardiovascular disease and death: an individual participant-level data meta-analysis. Lancet 2021;398:1053-64.To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/people-of-all-ages-benefit-from-drugs-to-lower-blood-pressure/.
A nanoparticle probe for the imaging of autophagic flux in live mice via magnetic resonance and near-infrared fluorescence
Authors: Howard H. Chen, Zehedina Khatun, Lan Wei, Choukri Mekkaoui, Dakshesh Patel, Sally Ji Who Kim, Asma Boukhalfa, Efosa Enoma, Lin Meng, Yinching I. Chen, Leena Kaikkonen, Guoping Li, Diane E. Capen, Parul Sahu, Anand T. N. Kumar, Robert M. Blanton, Hushan Yuan, Saumya Das, Lee Josephson, David E. Sosnovik
Journal: Nature Biomedical Engineering (2022)
Vasculature atrophy causes a stiffened microenvironment that augments epidermal stem cell differentiation in aged skin
Authors: Ryo Ichijo, Koichiro Maki, Mio Kabata, Teruasa Murata, Arata Nagasaka, Seiichiro Ishihara, Hisashi Haga, Tetsuya Honda, Taiji Adachi, Takuya Yamamoto, Fumiko Toyoshima
Journal: Nature Aging (2022)
Correspondence on ‘The 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-related disease’ by Wallace<i>et al</i>
Authors: Gözde Kübra Yardımcı, Beste Ekin Sandalcı Yıldırım, Bayram Farisoğulları, Levent Kilic, Omer Karadag
Journal: Annals of the Rheumatic Diseases (2022)

Table 1 Clinical phenotypes, general characteristics and 2019 ACR/EULAR Classification Criteria (AECC) for IgG4-RD Group 1. Pancreatohepatobiliary (n=10) Group 2. Retroperitoneum and aorta (n=38) Group 3. Head and neck limited (n=26) Group 4. Mikulicz and systemic (n=14) Undefined phenotype (n=8) P value Sex, male (%) 50.0 68.4 38.5 50.0 50.0 0.279 Age, median (IQR), years 49 (42-71) 61 (51-67) 55 (30-66) 61 (40-68) 45 (36-56) 0.101 Age at diagnosis, median (IQR), years 44 (36-66) 51(44-59) 50 (29-61) 48 (34-60) 40 (32-47) 0.358 IgG4 level, median (IQR), mg/dL 210 (86-25) 204 (138-361) 127 (56-300) 336 (65-683) 135 (77-160) 0.200 ESR/CRP ↑ (%) 70.0 76.3 38.5 71.4 75.0 0.028 Available biopsy at IgG4 involvement site (%) 80.0 71.1 84.6 100.0 87.5 0.
Gallic acid induces T-helper-1-like T<sub>reg</sub> cells and strengthens immune checkpoint blockade efficacy
Authors: Biaolong Deng, Biaolong Yang, Jieqiong Chen, Shuaiwei Wang, Weiqi Zhang, Yixian Guo, Yichao Han, Hecheng Li, Yongjun Dang, Yaqin Yuan, Xueyu Dai, Yuansheng Zang, Yangyang Li, Bin Li
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Foxp3 + regulatory T (T reg ) cells facilitate tumor immune evasion by forming a suppressive tumor microenvironment. Therefore, immune therapies promoting T reg fragility may greatly enhance immune checkpoint blockade (ICB) efficacy in cancers. Methods We have screened 2640 compounds and identified the gut microbial metabolite gallic acid, which promotes Foxp3 degradation and T reg instability by repressing Usp21 gene transcription. In vivo and in vitro experiments have been performed to explore the roles of Usp21 in T reg cells. Importantly, we treated tumor-bearing mice with gallic acid and anti-PD-1 antibody to explore the potential therapeutic value of gallic acid in clinical cancer immunotherapy. Results Mechanistically, gallic acid prevents STAT3 phosphorylation and the binding of phosphorylated STAT3 to Usp21 gene promoter. The deubiquitinated Usp21 and stabilized PD-L1 proteins boost the function of T reg cells. Combination of gallic acid and anti-PD-1 antibody, in colorectal cancer (CRC) treatment, not only significantly dampen T reg cell function by impairing PD-L1/PD-1 signaling and downregulating Foxp3 stability, but also promote CD8 + T cells’ production of IFN-γ and limited tumor growth. Conclusion Our findings have implications for improving the efficacy of ICB therapy in CRC by inducing T-helper-1-like Foxp3 lo T reg cells.